Discerning the Mauve

Factor

Woody McGinnis

London

October 1, 2006

Abram Hoffer Tapan Audhya William

Walsh

James Jackson Peter Lauda Roman

Lietha

Douglas Bibus Frances Jurnak

John McClaren Howard

Irene (Vicky)

Colquhoun

1920-2000

David Horrobin

1939-2003

Mauve History

Discovered in urine in 1958

Named for lilac-colored appearance on paper

chromatograms developed with Erhlich's

reagent

Labile and elusive

Abram Hoffer is the father of Mauve

Hoffer J Neuropsych

1961

Qualitative Mauve assay

All normals Mauve-negative

27/39 early schizophrenics positive

All 7 who recovered on niacinamide converted to

negative

Hoffer 1961

Mauve associates with relapses

Apparent role in other behaviors: ETOH,

depression

A "mentally retarded" mauve-positive child

responded dramatically to niacinamide

Hoffer and Mauve

Relatives should be tested

Preventive potential

10/14 criminal / deviant positives

740 patients: all recovered schizophrenics

negative, unrecovered 50% positive

Mauve in Schizophrenia

Hoffer 1961, 1963, 1966

Yutwiller 1962

O'Reilly 1965

Sohler 1967 x 2

High-Mauve and Behavior

Down syndrome

70%

Schizophrenia

40-70%

Autism 50%

ADHD 30%

ETOH 20-80%

Donald Irvine and Mauve

Dubbed it “Mauve Factor”

First to extract Mauve from urine

First to suggest pyrrole structure

Mis-identified Mauve twice

Animal experiments

Pfeiffer and Mauve

Introduced the colorimetric assay for Mauve using

kryptopyrrole as surrogate standard

Vitamin B6 and zinc to suppress Mauve and

improve clinical outcome, irrespective of

behavioral diagnosis

Mauve is hydroxyhemopyrrolin-

2-one (HPL), not kryptopyrrole

OHO

CH3

CH3

CH3N

CH3

NH H

C2H5 C2H5

H

Mauve (HPL) Kryptopyrrole

HPL by HPLC / MS and Colorimetric Assay

0

50

100

150

200

250

0 100 200 300 400 500

HPL by HPLC / MS in micrograms / deciliter

HP

L c

olo

rim

etr

ic e

qu

ivale

nts

in

mic

rog

ram

s /

decili

ter

n 54; r 0.97

Validation of Colorimetric Assay

HPL by HPLC / MS and Colorimetric Assay

0

20

40

60

80

100

120

0 50 100 150 200

HPL by HPLC / MS in micrograms / deciliter

HP

L C

olo

rim

etri

c E

qu

ival

ents

in

mic

rog

ram

s / d

ecili

ter

n 44; r 0.98

Validation of Colorimetric Assay

Mauve Testing

• Levels can fluctuate rapidly

during the day, so 24-hour

collection

• Variations in urine volume

can affect levels appreciably,

so normalize to SG or

creatinine

• Light and temperature labile,

so dark techniques,

ascorbate preservative,

freeze / overnight transport

HPL and B6 Activity

0.72

0.74

0.76

0.78

0.8

0.82

0.84

0 50 100 150 200

HPL in micrograms per deciliter

EG

OT

activ

ity r

atio

n 32; r neg 0.77

HPL and B6 Activity

Mauve Associations

Poor dream recall

Poor breakfast appetite

Nail spots (leukodynia)

Stretch marks (striae)

Pale skin / poor tanning

Acne, allergy, obesity

Mauve Associations

Course eyebrows

Knee and joint pain

Cold hands or feet

Abdominal tenderness

Constipation

Eosinophilia

Mauve Associations

Light / sound / odor intolerance

Tremor / shaking / spasms

Hypoglycemia / glucose intolerance

Delayed Puberty / Impotence

Amenorrhea / irregular periods

B6-responsive anemia

Mauve Associations

Stress intolerance

Emotional lability

Explosive anger

Anxiety / Withdrawal

Pessimism

Depression

Mauve AssociationsFamilial

Paranoia / Hallucinations

Perceptual

disorganization

Crime and deliquency

Substance abuse

Attention deficit / ADHD

Autism

Leukodynia in Zinc Deficiency

Colorimetric HPL and White-cell Zinc

3.5

4

4.5

5

5.5

6

6.5

7

0 10 20 30 40 50 60 70

HPL equivalents in micrograms / deciliter

Whi

te-c

ell z

inc

in n

anog

ram

s / l

iter

n 58; r neg 0.54

Colorimetric Mauve and WBC Zinc

HPL and Red-cell Zinc

0

2

4

6

8

10

12

14

16

18

0 50 100 150

HPL in micrograms / deciliter

Red

-cel

l zin

c in

mill

igra

ms

/ lite

r

HPL and RBC Zinc

n 37; r neg 0.69

HPL and Red-cell Zinc

0

2

4

6

8

10

12

14

16

18

1 10 100 1000

HPL in micrograms / deciliter

Red

-cel

l zin

c in

mg

/ lite

r HPL and RBC Zinc

HPL and Plasma Biotin

0

50

100

150

200

250

300

350

400

450

0 50 100 150

HPL in micrograms / deciliter

Pla

sma

biot

in in

nan

ogra

ms

/ lite

r

n 24; r neg 0.74

HPL and Plasma Biotin

Oxidative stress

Poor energetics Excitotoxicty

Emotional Stress

Oxidative Stress

Emotional stress

Oxidative stress

Tension-anxiety scores correlate

with oxidized DNA in blood

Meditation lowers blood lipid

peroxides

Increases free

radicals and

oxidized lipid,

protein and DNA

Brain peroxidation

prevented by

antioxidants

Immobilization-stress

Mauve and Stress

O’Reilly 1965: Hypothesized relationship

Ward 1973: Mauve proportionate to stress

Pfeiffer 1976: Mauve “is induced by stress”

Sohler unpublished animals studies

McCabe 1983: B6 and zinc “stress doses”

Audya 1992: US Navy cold water stress

HPL and Plasma Reduced Glutathione

0

1

2

3

4

5

6

0 50 100 150 200 250

HPL in micrograms / deciliter

Pla

sma

GS

H in

mic

rom

oles

/ lit

er

HPL and Plasma Reduced Glutathione

n 30; r neg 0.85

HPL and Heme

Graham 1979: HPL injection

acutely depresses hepatic

microsomal heme and

p450 levels

Ames 2002: Experimental

heme depression lowers

intracellular zinc, induces

NOS and increases

oxidative stress

Require Heme

Cystathionine

synthase

Catalase

Heme-hemopexin for

MT translation

Guanylate cyclase

Cytochromes

Sulfite reductase

NOS

Pyrrolase

HPL and Red-cell Catalase

0

50

100

150

200

250

300

350

400

0 50 100 150 200 250

HPL micrograms / deciliter

Cat

alas

e un

its /

min

/ m

g of

hem

oglo

bin

HPL and RBC Catalase

n 30; r neg 0.79

HPL and Plasma Nitric Oxide

0

20

40

60

80

100

120

140

160

180

200

0 50 100 150 200 250

HPL in micrograms / deciliter

Nitr

ic O

xide

in m

icro

mol

es /

liter

HPL and Plasma Nitric Oxide

n 30, r 0.60 improves to

0.96 if exclude outlier

Mauve and Cortisol

• Irvine 1972: corticosteroid

administration to rats produced

significant Mauve excretion.

• Increased intestinal permeability

from psychological stress is

mediated via endogenous

glucocorticoids

• Administration of corticosteroids

experimentally increases intestinal

permeability

Mauve from Microbes?

• Irvine 1973: Tetracycline

reversibly abolished Mauve

excretion in 4 subjects.

Kanamycin abolished or

significantly decreased

Mauve in 9 subjects.

• Monopyrroles are generated

by various bacteria, including

pseudomonas spp.

Oxidative

Stress Emotional Stress

Gut Permeability Low Zinc

HPL Regulatory

Heme

p450

Summary

• Mauve levels predict proportionately lower

functional B6 and zinc blood levels.

• Strong relationship to stress.

• Emerging evidence that Mauve is a biomarker

for oxidative stress.

• Possible enteric origin of Mauve.

• Need for prospective laboratory studies and

randomized clinical trials